Compounds for sustained release of orally delivered drugs

Abstract

Disclosed are methods for providing sustained systemic blood concentrations of orally delivered drugs. Still further, disclosed are compounds and pharmaceutical compositions that are used in such methods.

1 - 13 . (canceled) 
     
     
         14 . A pharmaceutical composition, which upon oral administration to an animal exhibits an extended pharmacokinetic profile through interaction with an enterohepatic circulation of the animal, comprising a pharmaceutically acceptable carrier, excipient or diluent and a conjugate of formula (I-b): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein:
 Q is CH 2 ; 
 R 1  is selected from the group consisting of hydrogen and OH; 
 R 2  is selected from the group consisting of hydrogen and OH; 
 D is derived from a compound having therapeutic or prophylactic activity when delivered to the systemic circulation of the animal, wherein the compound is selected from the group consisting of a GABA analog, a L-dopa derivative, catechol O-methyl transferase inhibitor, a drug containing a carboxyl group, a drug containing an amine group, and a drug containing a hydroxyl group; 
 Y b  represents —C(O)—; and 
 
         wherein Y b  and D are selected so that Y cleaves from D and releases the compound having therapeutic or prophylactic activity at a rate that provides for therapeutic concentrations of the compound in said animal for a period of at least about 10% longer than that achieved by oral delivery of the compound itself from a similar oral dosage form. 
       
     
     
         15 . The composition of  claim 14 , wherein D is derived from a GABA analog moiety having the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 103  is selected from the group consisting of hydrogen, an amino-protecting group, or a covalent bond linking the moiety to Y b ; 
 R 104  is hydrogen, or R 104  and R 109  together with the atoms to which they are attached form a heterocyclic ring; 
 R 105  and R 106  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
 R 107  and R 108  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R 107  and R 108  together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic ring; 
 R 109  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
 R 110  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
 R 111  is selected from the group consisting of carboxylic acid, carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidic heterocycle, sulfonic acid, hydroxamic acid and C(O)R 112 ; and 
 R 112  is a covalent bond linking the GABA analog moiety to either Y b , provided only one of R 103  and R 112  links the moiety to Y b ; 
 with the proviso that D is not derived from gabapentin. 
 
     
     
         16 . The composition of  claim 14 , wherein D is derived from an L-dopa derivative of formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 P is selected from: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 R 30  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 31  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and 
 each R 24  and R 25  are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R 24  and R 25  together with the carbon to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl ring; 
 with the proviso that one of the amino hydrogen atoms is removed to form a covalent bond to Y b . 
 
       
     
     
         17 . The composition of  claim 14 , wherein D is derived from a catechol O-methyl transferase inhibitor selected from entacapone, nitecapone, and tolcapone, optionally with one or two hydrogen atoms of two hydroxyl groups of the catechol group replaced with —C(O)R 304 , —C(O)OR 305  and/or —OCR 303 R 304 OC(O)R 305 ; wherein:
 R 303  and R 304  independently are members selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, and substituted heteroaryl; or R 303  and R 304  together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycle; or substituted heterocyclic ring; and   R 305  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, and substituted heteroaryl; or the OH group of the carboxyl moiety is replaced by —OR 304 ;   with the proviso that one of the amino hydrogen atoms is removed to form a covalent bond to Y b .   
     
     
         18 . The composition of  claim 14 , wherein D is derived from a drug containing a carboxyl group selected from alecapril, captopril, 1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylic acid, enalaprilic acid, lisinopril, N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine, pivopril, quinaprilat, (2R,4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid, (S)benzamido-4-oxo-6-phenylhexenoyl-2-carboxypyrrolidine, [2S-1[R*(R*))]]2α, 3αβ,7αβ]-1[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid, [3S-1[R*(R*))]], 3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolone carboxylic acid, tiopronin, cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone, cefixime, cefmenoxime, cefmetazole, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole, cefpirome, cefpodoxime, cefroxadine, cefsulodin, cefpiramide, ceftazidime, ceftezole, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, ceplialexin, cephaloglycin, cephaloridine, cephalosporin, cephanone, cephradine, latamoxef, amoxycillin, ampicillin, apalcillin, azidocillin, azlocillin, benzylpencillin, carbenicillin, carfecillin, carindacillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, methicillin, mezlocillin, nafcillin, oxacillin, phenethicillin, piperazillin, sulbenicllin, temocillin, ticarcillin, argatroban, melagatran, napsagatran, zanamivir, BCX-1812, acametacin, alclofenac, alminoprofen, aspirin, 4-biphenylacetic acid, bucloxic acid, carprofen, cinchofen, cinmetacin, clometacin, clonixin, diclenofac, diflunisal, etodolac, fenbufen, fenclofenac, fenclosic acid, fenoprofen, ferobufen, flufenamic acid, flufenisal, flurbiprofin, fluprofen, flutiazin, ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid, 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid, naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid, oxoprozin, pirprofen, prodolic acid, salicylic acid, salicylsalicylic acid, sulindac, suprofen, tiaprofenic acid, tolfenamic acid, tolmetin, zopemirac, ciprostene, 16-deoxy-16-hydroxy-16-vinyl prostaglandin E 2 , 6,16-dimethylprostaglandin E 2 , epoprostostenol, meteneprost, nileprost, prostacyclin, prostaglandins E 1 , E 2 , or F 2α  and thromboxane A 2 , acrosoxacin, cinoxacin, ciprofloxacin, enoxacin, flumequine, naladixic acid, norfloxacin, ofloxacin, oxolinic acid, pefloxacin, pipemidic acid, piromidic acid, aztreonam, imipenem, and meropenem. 
     
     
         19 . The composition of  claim 14 , wherein D is derived from a drug containing an amine group selected from acebutalol, albuterol, alprenolol, atenolol, bunolol, bupropion, butopamine, butoxamine, carbuterol, cartelolol, colterol, deterenol, dexpropanolol, diacetolol, dobutamine, exaprolol, exprenolol, fenoterol, fenyripol, labotolol, levobunolol, metolol, metaproterenol, metoprolol, nadolol, pamatolol, penbutalol, pindolol, pirbuterol, practolol, prenalterol, primidolol, prizidilol, procaterol, propanolol, quinterenol, rimiterol, ritodrine, solotol, soterenol, sulfiniolol, sulfinterol, sulictidil, tazaolol, terbutaline, timolol, tiprenolol, tipridil, tolamolol, thiabendazole, albendazole, albutoin, alendronate, alinidine, alizapride, amiloride, a minorex, aprinocid, cambendazole, cimetidine, cisapride, clonidine, cyclobenzadole, delavirdine, efegatrin, etintidine, fenbendazole, fenmetazole, flubendazole, fludorex, icadronate, lobendazole, mebendazole, metazoline, metoclopramide, methylphenidate, mexiletine, neridronate, nocodazole, oxfendazole, oxibendazole, oxmetidine, pamidronate, parbendazole, pramipexole, prazosin, procainamide, ranitidine, tetrahydrazoline, tiamenidine, tinazoline, tiotidine, tocamide, tolazoline, tramazoline, xylometazoline, dimethoxyphenethylamine, N-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-β-alanine, adrenolone, aletamine, amidephrine, amphetamine, aspartame, bamethan, betahistine, clorprenaline, chlortermine, dopamine, ephrinephrine etryptamine, fenfluramine, methyldopamine, norepinephrine, tocamide, enviroxime, nifedipine, nimodipine, triamterene, norfloxacin, pipedemic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1 piperazinyl)-1,8-napthyridine-3-carboxylic acid, and 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylic acid. 
     
     
         20 . The composition of  claim 14 , wherein D is derived from a drug containing a hydroxy group selected from allylestrenol, cingestol, dehydroepiandrosteron, dienostrol, diethylstilbestrol, dimethisteron, ethyneron, ethynodiol, estradiol, estron, ethinyl estradiol, ethisteron, lynestrenol, mestranol, methyl testosterone, norethindron, norgestrel, norvinsteron, oxogeston, quinestrol, testosterone, tigestol, dofexazepam, hydroxyzin, lorazepam, oxazepam, acetophenazine, carphenazine, fluphenazine, perphenyzine, piperaetazine, aclarubicin, cytarabine, decitabine, daunorubicin, dihydro-5-azacytidine, doxonibicin, epirubicin, estramustin, etoposide, fludarabine, gemcitabine, 7-hydroxychlorpromazin, nelarabine, neplanocin A, pentostatin, podophyllotoxin, tezacitabine, troxacitabine, vinblastin, vincristin, vindesin, buserilin, gonadoliberin, icatibrant, leuprorelin acetate, terphenadine, diflunisal, naproxol, paracetamol, salicylamide, salicyclic acid, azidamphenicol, azithromycin, camptothecin, cefamandol, chloramphenicol, clarithromycin, clavulanic acid, clindamycin, demeclocyclin, doxycyclin, erythromycin, gentamycin, imipenem, latamoxef, metronidazole, neomycin, novobiocin, oleandomycin, oxytetracyclin, tetracycline, thiamenicol, tobramycin; antivirals, acyclovir, d4C, ddC, DMDC, Fd4C, FddC, FMAU, FTC, 2′-fluoro-ara-dideoxyinosine, ganciclovir, lamivudine, penciclovir, SddC, stavudine, 5-trifluoromethyl-2′-deoxyuridine, zalcitabine, zidovudine, EB-1053, etidronate, ibandronate, olpadronate, residronate, YH-529, zolendronate, ciprokiren, enalkiren, ritonavir, saquinavir, terlakiren, arbaprostil, carboprost, misoprostil, prostacydin, 8-hydroxychlorimipramine, 2-hydroxyimipramine, sotarol, fenoldopam, piperidine, procyclidin, trihexyphenidal, cromolyn, glucocorticoids, betamethasone, budenosid, chlorprednison, clobetasol, clobetasone, corticosteron, cortisone, cortodexon, dexamethason, flucortolon, fludrocortisone, flumethasone, flunisolid, fluprednisolon, flurandrenolide, flurandrenolon acetonide, hydrocortisone, meprednisone, methylpresnisolon, paramethasone, prednisolon, prednisol, triamcinolon, triamcinolon acetonide, apomorphine, buprenorphine, butorphanol, codein, cyclazocin, hydromorphon, ketobemidon, levallorphan, levorphanol, metazocin, morphine, nalbuphin, nalinefen, naloxon, nalorphine, naltrexon, oxycodon, oxymorphon, pentazocin, asmazindol, pseudoephidrine, hydroxydion, propofol, acebutolol, albuterol, alprenolol, atenolol, betazolol, bucindolol, cartelolol, celiprolol, cetamolol, labetalol, levobunelol, metoprolol, metipranolol, nadolol, oxyprenolol, pindolol, propanolol, timolol, adrenalin, metaraminol, midodrin, norfenefrin, octapamine, oxedrin, oxilofrin, oximetazolin, phenylefrin, bamethan, clenbuterol, fenoterol, hexoprenalin, isoprenalin, isoxsuprin, orciprenalin, reproterol, salbutamol, terbutalin, carbuterol, dyphillin, etophyllin, fenoterol, pirbuterol, rimiterol, terbutalin, digitoxin, dobutamin, etilefrin, prenalterol, amphotericin B, chlorphenesin, nystatin, perimycin, acenocoumarol, dicoumarol, phenprocoumon, warfarin, bamethan, dipyrimadol, diprophyllin, isoxsuprin, vincamin, xantinol nicotinate, compactin, eptastatin, mevinolin, simvastatin, bromperidol, dithranol, ergotamine, ivermectin, metronidazole, secnizadole, nandrolon, propafenon, quinadine, quetiapine, serotonin, and silybin. 
     
     
         21 . The composition of  claim 14 , wherein Y b  cleaves at a rate that provides therapeutic concentrations of the compound in said animal for a period of at least about 50% longer than the oral delivery of the compound itself using a similar oral dosage form. 
     
     
         22 . The composition of  claim 14 , wherein Y b  cleaves at a rate that provides therapeutic concentrations of the compound in said animal for a period of at least about 100% longer than the oral delivery of the compound itself using a similar oral dosage form. 
     
     
         23 . The composition of  claim 14 , including a pharmaceutically acceptable excipient selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methyl cellulose. 
     
     
         24 . The composition of  claim 14 , including a carrier selected from the group consisting of a tablet, pill, soft gelatin capsule, hard gelatin capsule, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution and syrup. 
     
     
         25 . The composition of  claim 14 , wherein the composition contains up to 90% by weight of the conjugate.